EP3037128A1

EP3037128A1 - Implantable pulse generator system for vagal nerve stimulation

Info

Publication number: EP3037128A1
Application number: EP15199207.0A
Authority: EP
Inventors: Jie Lian; Lauren Kraiter; Alan Fryer; Andrew B. Kibler; Dirk Müssig; Larry Stotts; Warren Dabney; Jeffrey A. Von Arx
Original assignee: Biotronik SE and Co KG
Current assignee: Biotronik SE and Co KG
Priority date: 2014-12-22
Filing date: 2015-12-10
Publication date: 2016-06-29
Anticipated expiration: 2035-12-10
Also published as: EP3037128B1; US9895543B2; US20160175595A1

Abstract

The invention refers to an implantable pulse generator system that comprises a stimulation unit for generating a delivery of vagal nerve stimulation pulses, an activity sensor for determining an exertion level of a user and generating a metabolic demand-representing signal, at least one autonomic tone sensor for determining an autonomic status of a user and generating an autonomic status-representing signal, and a control unit that is connected to the stimulation unit, the activity sensor and the autonomic tone sensor, and that is adapted to control the stimulation unit depending on both, the metabolic demand-representing signal and the autonomic status-representing signal.

Description

The application refers to an implantable pulse generator system for autonomic adaptive control of vagal nerve stimulation (VNS).
Vagal nerve stimulation (VS) systems and methods are inter alia disclosed in US 7,778,703 , US 7,783,362 , US 8,401,604 , US 8,473,068 , US 8,712,547 , US 2013/0184773 and US 2014/0155949 as well as in Robert J. Henning et al. "Vagal nerve stimulation increases right ventricular contraction and relaxation and heart rate", Cardiovascular Research 32, 1996, 846-853.
It is an object of the invention to provide an improved system for vagal nerve stimulation.
According to the invention, this object is achieved by means of an implantable pulse generator system that comprises a stimulation unit for generating a delivery of vagal nerve stimulation pulses, an activity sensor for determining an exertion level of a user and generating a metabolic demand-representing signal, at least one autonomic tone sensor for determining an autonomic status of a user and generating an autonomic status-representing signal, and a control unit that is connected to the stimulation unit, the activity sensor and the autonomic tone sensor, and that is adapted to control the stimulation unit depending on both, the metabolic demand-representing signal and the autonomic status-representing signal.
By means of such implantable pulse generating system, it is possible to provide for a closed loop control of vagal nerve stimulation to achieve autonomic balance. The implantable pulse generator system according to the invention enables adaptive control of vagal nerve stimulation (VNS) in order to achieve optimal balance between VNS and the patient's exertion level.
Closed loop control of vagal nerve stimulation (VNS) is desired to maximize the beneficial effect for heart failure treatment while minimizing the risk of severe sympathetic depression. On one hand, it is preferred to activate and/or enhance VNS intensity in order to lower a patient's resting sympathetic tone. On the other hand, it is important to limit and/or inhibit VNS in order to preserve an appropriate degree of sympathetic activation when the patient is engaging in physical or mental activities. However, maintaining the optimal balance between VNS and patient's exertion level remains a technical challenge.
According to the invention, adaptive control of the delivery of vagal nerve stimulation (VNS) is provided by adapting the VNS to both the autonomic status and cardiovascular demand of the patient. The implantable pulse generator comprises at least one activity sensor for measuring the patient's exertion level and at least one autonomic tone sensor for detecting the autonomic status of the patient.
According to one embodiment of the invention, the implantable pulse generator is adapted to be capable of inducing either an increase in vagal tone or an increase in sympathetic tone. Accordingly, an implantable pulse generator system is preferred wherein the control unit is adapted to control the stimulation unit to generate stimulation pulses having stimulation parameters that are configured to induce a VNS effect that is either an increase in vagal tone or an increase in sympathetic tone, depending on both, the cardiovascular demand representing signal and the autonomic status representing signal.
Adaptations to alter the effect of VNS may be stimulation parameters such as amplitude or pulse width, and/or selection of stimulating electrode(s) on the vagal nerve stimulator. Accordingly, an implantable pulse generator system is preferred wherein the control unit and the stimulation unit are adapted to alter the effect of VNS by adjusting stimulation parameters including at least one of amplitude, pulse width, pulse timing and/or selection of stimulating electrodes. Selection of stimulating electrodes may cause preferential activation of sub-regions of the vagus nerve in close proximity to the selected electrode, or, depending on the electrode geometry, may cause unidirectional propagation of action potentials selectively in either the efferent or afferent direction, using electrode geometries familiar to those skilled in the art.
The response of each electrode or stimulation parameter set can be determined by characterization prior to or during therapy and the result of characterization applied to the automatic adaptive control disclosed herein. Accordingly, it is preferred if the control unit is programmable.
According to a further aspect, if the activity sensor indicates a patient is at rest but the sympathetic tone is elevated, then VNS is activated or its intensity is increased in order to enhance the vagal tone to achieve autonomic balance. According to still a further aspect, if the activity sensor indicates the patient is involved in exertion activities but the sympathetic tone is suppressed, then VNS is adapted to decrease vagal tone or enhance sympathetic tone so that the patient is supported in physical or mental activities without artificially induced limitation on exertion.
Accordingly, it is preferred if the control unit is adapted to control the stimulation unit to generate stimulation pulses having stimulation parameters that are configured to induce an increase in vagal tone if the metabolic demand-representing signal of the activity sensor indicates a low demand and the autonomic status-representing signal of the autonomic tone sensor indicates that the sympathetic tone is elevated.
According to a further aspect, it is preferred if the control unit is adapted to control the stimulation pulse unit to generate stimulation pulses having stimulation parameters that are configured to induce a decrease in vagal tone and/or an increase in sympathetic tone if the metabolic demand-representing signal of the activity sensor indicates an elevated metabolic demand and the autonomic status-representing signal of the autonomic tone sensor indicates that the sympathetic tone is suppressed.
The activity sensor for providing a metabolic demand-representing signal preferably comprises at least one of an accelerometer, a CLS sensor (Closed Loop Stimulation sensor), a temperature sensor, a tissue oxygenation sensor, and/or a minute ventilation sensor. A CLS sensor has been shown to be able to measure both physical and mental exertion of a patient.
The CLS sensor and/or the minute ventilation sensor preferably comprise or are connected to an impedance determination unit that is configured to determine an intracardiac or a transthoracic impedance or both.
By means of such impedance determination unit, it is possible to determine both, an intracardiac impedance and a transthoracic impedance. Transthoracic impedance can be evaluated to determine a tidal volume (Minute volume) and breathing rate (minute rate). Intracardiac impedance can be used to determine stroke volume, contractility, heart rate and further metrics of a heart.
The Closed Loop Stimulation sensor is configured to determine a course of intracardiac impedance and to compare the course with a reference course and/or to determine a maximum of the first derivative of the course of intracardiac impedance.
The autonomic tone sensor preferably is configured to process IEGM signals representing an intracardiac electrogram (IEGM). The autonomic tone sensor preferably is adapted to determine one or more of the following metrics from IEGM signals: intrinsic heart rate (HR), heart rate variability (HRV), intrinsic atrioventricular (AV) conduction time, QRS duration and/or P wave duration.
Alternatively, the autonomic tone sensor preferably is configured to process heart sound signals that reflect contraction-induced pressure waves, intra-cardiac pressure and/or an impedance signal reflecting myocardial contractility.
As an additional alternative, the autonomic tone sensor is preferably configured to process nerve signals that reflect the patient's intrinsic nerve activity. The intrinsic nerve sensing could be near the site of stimulation or at a different nerve site. Target neurologic locations include but are not limited to the stellate ganglion, vagus nerve, or medulla oblongata. Alternatively or additionally, the autonomic tone sensor is configured to process signals that reflect the patient's state of blood pressure, vasodilatation and/or vasoconstriction.
Thus, the autonomic tone sensor measures a physiological signal that is known to be affected by the autonomic status. For example, the device can use IEGM sensing electrodes to measure the intrinsic heart rate (HR) which is directly modulated by the autonomic status of the patient. Elevated sympathetic tone leads to increase in HR and vice versa. In another example, the intrinsic AV conduction time is known to be affected by the autonomic status of the patient. Elevated sympathetic tone is associated with decrease in intrinsic AV conduction time and vice versa. Another measure of autonomic tone could be achieved by measuring the delay from beginning of electrical QRS signal to a vibration pulse measured at the cervical level via an accelerometer attached or adjacent to a VNS cuff. Such vibration pulse reflects a local change of blood pressure that is caused in a cervical blood vessel by myocardial contraction of the heart. The delay between the QRS signal and the vibration pulse is related to cardiac contractility and current autonomic state relative to a previous autonomic state may be derived. Other physiological parameters can also be measured for the evaluation of autonomic status, including but are not limited to, heart rate variability, QRS duration, P wave duration, heart sound (contraction-induced pressure waves), intra-cardiac pressure, etc.
A natural contraction of a heart chamber can be similarly detected by the evaluating electrical signals sensed by the sensing channels. In the sensed electrical signal the depolarization of an atrium muscle tissue is manifested by occurrence of a P-wave. Similarly, the depolarization of ventricular muscle tissue is manifested by the occurrence of a R-wave. The detection of a P-wave or a R-wave signifies the occurrence of intrinsic atrial, As, or ventricular, Vs events, respectively. The AV-delay is the time period between an atrial event and a prescribed point of time of a ventricular event. The heart rate (HR) is inverse to the time period between consecutive ventricular events. The heart rate variability (HRV) is based on the distribution of heart rate intervals over a fixed period of time; high frequency variations in heart rate are mediated by parasympathetic tone, while low frequency variations in heart rate are influenced by both parasympathetic and sympathetic tone.
In a healthy heart, initiation of the cardiac cycle normally begins with depolarization of the sinoatrial (SA) node. This specialized structure is located in the upper portion of the right atrium wall and acts as a natural "pacemaker" of the heart. In a normal cardiac cycle and in response to the initiating SA depolarization, the right atrium contracts and forces the blood that has accumulated therein into the ventricle. The natural stimulus causing the right atrium to contract is conducted to right ventricle via the atrioventricular node (AV node) with a short, natural delay, the atrioventricular delay (AV-delay). Thus, a short time after the right atrial contraction (a time sufficient to allow the bulk of the blood in the right atrium to flow through the one-way valve into the right ventricle), the right ventricle contracts, forcing the blood out of the right ventricle to body tissue. A typical time interval between contraction of the right atrium and contraction of the right ventricle might be 120 ms; a typical time interval between contraction of the right ventricle and the next contraction of the right atrium might be 800 ms. Thus, it is an right atrial contraction (A), followed a relatively short time thereafter by a right ventricle contraction (V), followed a relatively long time thereafter by the next right atrial contraction, that produces the desired AV synchrony. Where AV synchrony exists, the heart functions very efficiently as a pump in delivering life-sustaining blood to body tissue; where AV synchrony is absent, the heart functions as an inefficient pump (largely because the right ventricle is contracting when it is not filled with blood).
According to a further aspect, the object of the invention is achieved by a method for vagal nerve stimulation, the method comprising:

determining an exertion level indicating metabolic demand
determining an autonomic status level, and
delivering nerve stimulation pulses depending on both, the determined exertion level and the autonomic status level.

Preferably, nerve stimulation pulses having stimulation parameters that are configured to induce an increase in vagal tone are delivered if the cardiovascular demand representing signal of the activity sensor indicates a low demand and the autonomic status representing signal of the autonomic tone sensor indicates that the sympathetic tone is elevated.
It is further preferred that nerve stimulation pulses having stimulation parameters configured to induce a decrease in vagal tone and/or an increase in sympathetic tone are delivered, if the cardiovascular demand representing signal of the activity sensor indicates an elevated cardiovascular demand and the autonomic status representing signal of the autonomic tone sensor indicates that the sympathetic tone is suppressed.
The above and other aspects, features and advantages of the present invention will be more apparent from the following more particular description thereof, presented in conjunction with the following drawings wherein:

Fig. 1: shows a vagal nerve stimulation system.
Fig. 2: illustrates an implantable pulse generator for heart stimulation and vagus stimulation;
Fig. 3: is a schematic block diagram of an implantable pulse generator (IPG) used in the system of Fig. 1.
Fig. 4: is a schematic block diagram of an implantable pulse generator (IPG) used in the system of Fig. 1 showing an alternative electrode arrangement.
Fig. 5: is a schematic representation of a nerve stimulation electrode pole arrangement as used in the system of Fig. 1 arranged on a quadripolar stimulating cuff.
Fig. 6: is a high level flowchart illustrating the concept of adaptive close loop control ofVNS
Fig. 7: illustrates experimental results demonstrating autonomic control (as evidenced by heart rate) modulated by stimulation parameter, in this case VNS amplitude.
Fig. 8: illustrates experimental results demonstrating autonomic control (as evidenced by heart rate) modulated by electrode selection.

The following description is of the best mode presently contemplated for carrying out the invention. This description is not to be taken in a limiting sense, but is made merely for the purpose of describing the general principles of the invention. The scope of the invention should be determined with reference to the claims.
Fig. 1 illustrates an implantable pulse generator system for vagal nerve stimulation. The system comprises an implantable medical device 10 that is an implantable pulse generator (IPG). The implantable medical device 10 is connected to a nerve stimulation electrode cuff 100 via a nerve stimulation electrode lead 102.
The implantable pulse generator 10 can be wirelessly programmed by an external programmer 92 via a MICS-band link (or equivalent). The implantable pulse generator 10 can also communicate with a bedside Patient Messenger 90 via a similar link. Arrhythmia detection, blood pressure waveform changes, and the other relevant diagnostic parameters described before can be transmitted to the bedside Patient Messenger 90 who can alert a Home Monitoring/Remote Programming Center, if medical attention is required.
In figure 2 the implantable medical device (also referred to as implantable pulse generator) is a three chamber biventricular pacemaker and cardioverter/defibrillator that is connected to pacing/sensing leads placed in a heart 12. The implantable medical device further is a vagal nerve stimulation pulse generator that is connected to cuff electrode 100 by means of nerve stimulation electrode lead 102.
As shown in figure 2, the preferred embodiment is to couple a vagal nerve stimulation pulse generator with an implantable bi-ventricular defibrillator.
The implantable medical device 10 is electrically coupled to heart 12 by way of leads 14, 16 and 30.
Lead 14 is a right atrial electrode lead that has a pair of right atrial electrodes 22 and 24 that are in contact with the right atria 26 of the heart 12.
Lead 16 is a right ventricular electrode lead that has a pair of ventricular stimulation and sensing electrodes 18 and 20 that are in contact with the right ventricle 28 of heart 12. Further, a ventricular defibrillation shock coil 38 and an atrial defibrillation shock coil 40 are arranged on lead 16.
Electrodes 22 and 18 are tip electrodes at the very distal end of leads 14 and 16, respectively. Electrode 22 is a right atrial tip electrode RA Tip and electrode 18 is a right ventricular tip electrode. Electrodes 24 and 20 are ring electrodes in close proximity but electrically isolated from the respective tip electrodes 22 and 18. Electrode 24 forms a right atrial ring electrode RA Ring and electrode 20 forms a right ventricular ring electrode RV Ring. Atrial cardioversion shock coil 40 is a coil electrode providing a relatively large geometric area when compared to the stimulation electrodes 18, 20, 22 and 24.
Lead 30 is a left ventricular electrode lead passing through the coronary sinus of heart 12 and having left ventricular ring electrodes LV RING 31, 32 and 33 and a left ventricular tip electrode LV TIP 34. Further, a left ventricular defibrillation shock coil 36 is arranged on lead 30. It is noted that the number of left ventricular ring electrodes may vary depending on the electrode lead that is used. In the context of figures 2 and 3, one left ventricular ring electrode LV-RING is referred to the acts as pars pro toto.
Implantable medical device 10 has a generator housing 42 made from electrically conductive material such as titanium that can serve as a large surface electrode IMD CASE.
The plurality of electrodes 18, 20, 22, 24, 31, 32, 33, 34, 36, 38 and 40 connected to implantable medical device 10 together with case 42 allow for a number of different electrode configurations for measuring intrathoracic and intracardiac impedance.
For each individual one of the intracardiac impedance measurements, injecting a forcing function from a right ventricular ring electrode to a left ventricular ring electrode and measuring a response function between the same electrodes (bipolar configuration; see figure 2) or, for instance, a right ventricular tip electrode and a left ventricular tip electrode (quadripolar configuration; see figure 3) is possible. Further impedance measurement vectors (resulting from different impedance measurement electrode combinations) are possible.
Referring to figure 3 a simplified block diagram of an implantable medical device 10 is shown. During operation of the pacemaker leads 14, 16 and 30 are connected to respective output/input terminals of pacemaker 10 as indicated in figure 2 and carry stimulating pulses to the tip electrodes 18, 22 and 34 from a right atrial stimulation pulse generator A-STIM 50, a right ventricular pulse generator RV-STIM 52 and a left ventricular pulse generator LV-STIM 54, respectively. Further, electrical signals from the right atrium are carried from the electrode pair 22 and 24, through the lead 14, to the input terminal of a right atrial channel sensing stage A-SENS 56; and electrical signals from the right ventricle are carried from the electrode pair 18 and 20, through the lead 16, to the input terminal of a right ventricular sensing stage RV-SENS 58. Likewise electrical signals from the left ventricle are carried from the electrode pair 32 and 34, through the lead 30, to the input terminal of a left ventricular sensing stage LV-SENS 60.
Controlling the implantable medical device 10 is a control unit CTRL 62 that is connected to sensing stages A-SENS 56, RV-SENS 58 and LV-SENS 60 and to stimulation pulse generators A-STIM 50, RV-STIM 52 and LV-STIM 54. Control unit CTRL 62 receives the output signals from the atrial sensing stage A-SENS 56, from the right ventricular sensing stage RV-SENS 58 and from the left ventricular sensing stage LV-SENS 60. The output signals of sensing stages A-SENS 56, RV-SENS 58 and LV-SENS 60 are generated each time that a P-wave representing an intrinsic atrial event or an R-wave representing an intrinsic ventricular event, respectively, is sensed within the heart 12. An As-signal is generated, when the atrial sensing stage A-SENS 56 detects a P-wave and a RVs-signal is generated, when the right ventricular sensing stage RV-SENS 58 detects an R-wave. These sense events are used by control unit CTRL 62 as fiducial points of the respective intracardiac electrograms picked up by the sensing stages A-SENS 56, RV-SENS 58 and LV-SENS 60, respectively.
Control unit CTRL 62 also generates trigger signals that are sent to the atrial stimulation pulse generator A-STIM 50, the right ventricular stimulation pulse generator RV-STIM 52 and the left ventricular stimulation pulse generator LV-STIM 54, respectively. These trigger signals are generated each time that a stimulation pulse is to be generated by the respective pulse generator A-STIM 50, RV-STIM 52 or LV-STIM 54. The atrial trigger signal is referred to simply as the "A-pulse", and the ventricular trigger signal is referred to as the "RV-pulse" or the "LV-pulse", respectively. During the time that either an atrial stimulation pulse or ventricular stimulation pulse is being delivered to the heart, the corresponding sensing stage, A-SENS 56, RV-SENS 58 and/or LV-SENS 60, is typically disabled by way of a blanking signal presented to these amplifiers from the control unit CTRL 62, respectively. This blanking action prevents the sensing stages A-SENS 56, RV-SENS 58 and LV-SENS 60 from becoming saturated from the relatively large stimulation pulses that are present at their input terminals during this time. This blanking action also helps prevent residual electrical signals present in the muscle tissue as a result of a stimulation pulse delivered from pacemaker 10 from being interpreted as P-waves or R-waves.
Furthermore, atrial sense events As recorded shortly after delivery of a ventricular stimulation pulses during a preset time interval called post ventricular atrial refractory period (PVARP) are generally recorded as atrial refractory sense event Ars but ignored.
Control unit CTRL 62 comprises circuitry for timing ventricular and/or atrial stimulation pulses according to an adequate stimulation rate that can be adapted to a patient's hemodynamic need as pointed out below.
Control unit CTRL 62 further comprises an autonomic tone sensor 82 that is connected to right ventricular sensing stage 58. The autonomic tone sensor 82 is configured to process IEGM signals representing an intracardiac electrogram (IEGM). The autonomic tone sensor 82 preferably is adapted to determine one or more of the following metrics from IEGM signals: intrinsic heart rate (HR), heart rate variability (HRV), intrinsic atrioventricular (AV) conduction time, QRS duration and/or P wave duration.
Still referring to figure 3, the implantable medical device 10 includes a memory circuit MEM 64 that is coupled to the control unit CTRL 62 over a suitable data/address bus ADR. This memory circuit MEM 64 allows certain control parameters, used by the control unit CTRL 62 in controlling the operation of the implantable medical device 10, to be programmably stored and modified, as required, in order to customize the implantable medical device's operation to suit the needs of a particular patient. Such data includes the basic timing intervals used during operation of the pacemaker 10 and AV delay values and hysteresis AV delay values in particular.
Further, data sensed during the operation of the implantable medical device 10 may be stored in the memory MEM 64 for later retrieval and analysis.
A telemetry circuit TEL 66 is further included in the implantable medical device 10. This telemetry circuit TEL 66 is connected to the control unit CTRL 62 by way of a suitable command/data bus. Telemetry circuit TEL 66 allows for wireless data exchange between the implantable medical device 10 and some remote programming or analyzing device which can be part of a centralized service center serving multiple pacemakers.
The implantable medical device 10 in figure 3 is referred to as a three chamber pacemaker/cardioverter/defibrillator because it interfaces with the right atrium 26, the right ventricle 28 and the left ventricle of the heart 12. Those portions of the pacemaker 10 that interface with the right atrium, e.g., the lead 14, the P-wave sensing stage A-SENSE 56, the atrial stimulation pulse generator A-STIM 50 and corresponding portions of the control unit CTRL 62, are commonly referred to as the atrial channel. Similarly, those portions of the pacemaker 10 that interface with the right ventricle 28, e.g., the lead 16, the R-wave sensing stage RV-SENSE 58, the ventricular stimulation pulse generator RV-STIM 52, and corresponding portions of the control unit CTRL 62, are commonly referred to as the ventricular channel.
In order to be able to determine a metabolic demand of a patient, the pacemaker 10 further includes a physiological sensor ACT 68 that is connected to the control unit CTRL 62 of the pacemaker 10. While this sensor ACT 68 is illustrated in figure 3 as being included within the pacemaker 10, it is to be understood that the sensor may also be external to the implantable medical device 10, yet still be implanted within or carried by the patient. A common type of activity sensor is an accelerometer, such as a micro electromechanical system (MEMS), mounted in the case of the pacemaker. Other types of physiologic sensors are also known, such as sensors that sense the oxygen content of blood, respiration rate, blood pH, intracardiac impedance changes, and the like. The type of activity sensor used is not critical to the present invention. Any sensor capable of sensing some physiological parameter relatable to physical activity and/or metabolic demand of a patient can be used. Such physiological sensors are commonly used with "rate-responsive" pacemakers in order to adjust the rate of the pacemaker in a manner that tracks the physiological needs of the patient. The output of sensor 68 represents an activity level.
According to a typical embodiment, the activity sensor 68 is an accelerometer. According to another embodiment, the activity sensor 68 is the CLS sensor, which has been shown to be able to measure both physical and mental exertion of the patient. Yet in another embodiment, the activity sensor 68 is the minute ventilation sensor, which may be based on the measurement of trans-thoracic impedance signal.
By means of the output signal of activity sensor 68 the control unit 62 is able to assign each intrinsic heart rate to an activity thus enabling collection of intrinsic heart rate value for a patient's state of rest and a patient's state of exercise separately.
For impedance measurement, an impedance determination unit 70 is provided. Impedance determination unit 70 comprises a constant current source 72 that is connected or can be connected to electrodes for intracorporeal placement as shown in figure 1. In order to allow for a plurality of impedance measurement electrode configurations, preferably some means of switching is provided between the constant current source 72 and the electrode terminals of the implantable medical device 10. The switch is not shown in figure 2. Rather, particular impedance measurement configurations are shown as examples.
Similarly, a voltage measuring unit 74 for measuring a voltage corresponding to a current fed through a body by said constant current source is provided and can be connected to a number of electrodes although a switch for switching between these configurations is not shown in figure 2.
As an alternative to constant current source 72 a constant voltage source can be provided to generate the forcing function. Then, the measuring unit will be adapted to measure a current strength of a current fed through a body by said constant voltage source.
Both, constant current source 72 and voltage measurement unit 74, are connected to an impedance value determination unit 76 that is adapted to determine an impedance value for each measuring current pulse delivered by the constant current source 72.
Further, an evaluation unit 78 is provided either as a separate unit or as part of control unit CTRL 62 as depicted in Figure 2. The evaluation unit 78 is connected to said impedance determination unit 70 and is adapted to evaluate a sequence of consecutive impedance values determined by said impedance determination unit 70. The evaluation unit 78 comprises a signal generator module (not shown) to construct the intracardiac impedance or conductance signal reflecting the time course of the impedance determination unit's output signal and its derivative.
The evaluation unit 78 further comprises a filter module (not shown) to filter the intracardiac impedance signal.
The evaluation unit 78 is further connected to the right ventricular stimulation stage RV-STIM 52 and the right ventricular sensing stage RV-SENS 58 in order to receive signals representing cardiac events, namely right ventricular stimulation events RVp or right ventricular sense events RVs, respectively.
The constant current source 72 has its two poles connected to different connectors for different electrodes as for example the right ventricular ring electrode and the left ventricular ring electrode (Fig. 2) or the left ventricular tip electrode and the right ventricular tip electrode (Fig. 3). The voltage measuring unit 74 has two poles connected to, for example, a connector for the left ventricular ring electrode and the right ventricular ring electrode (Fig. 2) or the left ventricular ring electrode and the right ventricular ring electrode (Fig. 3). Thus, a bipolar or a quadripolar impedance measurement configuration is established.
Impedance measurement is carried out by injecting a constant current and sampling the resulting voltage.
The measuring current is preferably pulsed. Typically, the measuring current will feature biphasic pulses wherein two constant current pulses of opposite polarity form one pulse packet. Two consecutive pulse packages between two consecutive pulse packets a time gap is provided, which is significantly longer than the duration of one pulse packet. The constant current pulses within one pulse packet are each of the same intensity and of same duration. They only have different polarities. The typical value for the intensity of the constant current pulses is between 50 µA and 600 µA. The typical pulse duration of a single constant current pulse is about 15 µs.
The time gap between each two consecutive pulse packets may be 500 times longer than the duration of one constant current pulse. The two constant current pulses of opposite polarity within one pulse packet may not follow immediately each other but may have a time gap there between. This time gap however, will be very short compared to the time gap between two consecutive pulse packets. Furthermore, consecutive pulse packets may be face alternating such that a first pulse packet for example will begin with a positive constant current pulse whereas the following pulse packet will begin with a negative constant current pulse and end with a positive constant current pulse.
Via intracardiac impedance measurement, control unit 62 is able to determine a stroke volume.
Via intrathoracic impedance measurement control unit 62 is able to determine a tidal volume and a ventilation rate (breathing rate) in a manner generally known to the skilled person.
Implantable pulse generator 10 further comprises a nerve stimulation unit 80 for generating nerve stimulation pulses. The nerve stimulation unit 80 is connected to and controlled by control unit 62. When in use, nerve stimulation unit 80 is further connected to a nerve stimulation electrode lead which preferably is a quadripolar lead comprising four electric conductors the can connect the nerve stimulation unit 80 to corresponding stimulation electrode poles of a nerve stimulation electrode cuff.
Figure 5 discloses a nerve stimulation electrode pole arrangement as used in the system of Fig. 1. Four stimulation electrode poles 104 are arranged on the quadripolar stimulation electrode cuff 100. Figure 5 further illustrates cross-section of a nerve and stimulating vectors that can be achieved by means of electrode poles 104. The illustrated stimulation vectors are those used for obtaining the nerve stimulation results illustrated in Figure 8.
According to this invention, the autonomic tone sensor measures a physiological signal that is known to be affected by the autonomic status. For example, the device can use IEGM sensing electrodes to measure the intrinsic heart rate (HR) which is directly modulated by the autonomic status of the patient. Elevated sympathetic tone leads to increase in HR and vice versa. In another example, the intrinsic AV conduction time is known to be affected by the autonomic status of the patient. Elevated sympathetic tone is associated with decrease in intrinsic AV conduction time and vice versa. Another measure of autonomic tone could be achieved by measuring the delay from beginning of electrical QRS signal to a vibration pulse measured at the cervical level via an accelerometer attached or adjacent to a VNS cuff. The delay is related to cardiac contractility and current autonomic state relative to a previous autonomic state may be derived. Other physiological parameters can also be measured for the evaluation of autonomic status, including but are not limited to, heart rate variability, QRS duration, P wave duration, heart sound (contraction-induced pressure waves), intra-cardiac pressure, ganglionic and axonal nervous depolarization, etc.
A novel aspect of this invention arises from the discovery that it is possible to exert bimodal control of autonomic tone via a singular stimulating cuff electrode implanted at the cervical vagus level. Although the vagus is understood by those skilled in the art to be primarily a parasypathetically active nerve, the cervical vagus contains a small percentage of sympathetically active fibers. The inventors have demonstrated that the action of these fibers may be selectively evoked via selection of stimulation parameters and by applying a multi-electrode nerve stimulation electrode cuff, allowing regional selectivity.
Figures 7 and 8 show experimental evidence of bimodal autonomic tone control via VNS. Figure 7 depicts amplitude-based selective action of VNS seen in preclinical work, and figure 8 depicts stimulating electrode-based selectivity of VNS, using a quadripolar stimulating electrode, shown in Figure 5.
Three typical scenarios are illustrated below. In one example, the activity sensor indicates the patient's exertion level is low (e.g. sensor-indicated heart rate is low), but the measured intrinsic HR is high or the AV conduction time is short. This scenario suggests patient's sympathetic tone is high although patient is at rest. Thus VNS is activated or its intensity is increased to suppress the sympathetic activity. Intensity can be increased by increasing stimulation parameters such as amplitude, pulse width, or frequency and/or number of pulses delivered.
In another example, the activity sensor indicates patient's exertion level is increased (e.g. sensor-indicated activity level is high), but the measured intrinsic HR is low or the AV conduction time is long. This scenario suggests the suppression of sympathetic tone despite patient's exertion effort. Thus VNS is deactivated or its intensity is reduced to relieve the sympathetic inhibition. In the scenario where modulation of VNS is controlled by a CLS signal, larger differential area between CLS impedance waveform and the reference impedance waveform indicates higher feedback gain, which leads to greater adjustment of the VNS intensity. In the scenario where modulation of VNS is controlled by an accelerometer, a higher level of motion indicates higher feedback gain and greater adjustment of VNS intensity. Intensity can be increased by increasing stimulation parameters such as amplitude, pulse width, or frequency and/or number of pulses delivered.
In a third example, a patient activity sensor comprised of a motion sensor and/or CLS sensor determines that the patient's metabolic demand has increased but the measured HR is low or the AV conduction time is long. In addition, parasympathetic enhancement has via VNS has already been reduced or turned off. This scenario suggests that the patient may benefit from temporarily enhanced sympathetic tone to support metabolic function. Thus VNS is adapted to enhance sympathetic tone by a modification of stimulation parameters, as amplitude, pulse width, and/or pulse timing, or stimulation electrode of the VNS system which selectively activates a desired subset of vagal fibers, and/or the direction of propagation of the activation of desired fibers. Thus, the increased metabolic demand is positively supported by adaptation of VNS parameters.
Control 62 is adapted to control nerve stimulation pulse generator 80 accordingly. Operation of control unit 62 is illustrated by means of the flow diagram in figure 6.
According to the flow chart in Fig. 6, implantable pulse generator 10 monitors exertion and autonomic status (600). Implantable pulse generator 10 then decides whether or not the exertion has increased (602). If exertion has increased, implantable pulse generator 10 determines whether there is an insufficient increase in sympathetic tone (604). If that is the case, implantable pulse generator 10 determines whether or not a parasympathetically enhancing vagal nerve stimulation is active (606). Should that be the case, implantable pulse generator 10 controls nerve stimulation unit 80 so as to diminish or to deactivate parasympathetic vagal nerve stimulation (608). Alternatively, if parasympathetically enhancing vagal nerve stimulation is not active, implantable pulse generator 10 controls nerve stimulation unit 80 so as to enhance or activate a sympathetic vagal nerve stimulation (610). In case there is no insufficient increase in sympathetic tone (604), implantable pulse generator 10 returns to monitoring exertion and autonomic status (600). In case implantable pulse generator 10 determines no increased exertion (602), implantable pulse generator 10 further determines whether or not there is an undesired increase in sympathetic tone (612). Should that be the case, implantable pulse generator further determines whether or not sympathetically enhancing vagal nerve stimulation is active (614). Should the latter be the case, implantable pulse generator 10 controls a nerve stimulation unit 80 so as to diminish or deactivate sympathetic vagal nerve stimulation (616). Otherwise, implantable pulse generator 10 controls nerve stimulation unit 80 so as to enhance or activate parasympathetic vagal nerve stimulation (618).
Should the implantable pulse generator 10 determine that there is no increased exertion and there is no undesired increase in sympathetic tone, implantable pulse generator 10 returns to monitoring exertion and autonomic status (600).
This invention teaches a novel apparatus and method for close loop control of VNS. It offers a unique solution to a challenging problem - to optimally balance the VNS and cardiovascular exertion via bimodal control of autonomic tone via VNS, which has not been addressed by any prior art.
The concept described in this disclosure aligns with and further extends the CLS technology. Instead of using CLS impedance signal to adjust pacing rate, this invention uses this signal as a feedback to modulate the VNS, thus offering a different way to close the gap of autonomic control loop which is often compromised in the heart failure patients.

Reference list

10: Implantable medical device, implantable pulse generator
12: Heart
14: Right atrial electrode lead
16: Right ventricular electrode lead
18: Right ventricular tip electrode
20: Right ventricular ring electrode
22: Right atrial tip electrode
24: Right atrial ring electrode
26: Right atrium
28: Right ventricle
30: Left ventricular electrode lead
31, 32, 33: Left ventricular ring electrodes
34: Left ventricular tip electrode
36: Left ventricular defibrillation shock coil
38: Ventricular shock coil
40: Atrial shock coil
42: Generator housing
50: Atrial stimulation pulse generator
52: Right ventricular stimulation pulse generator
54: Left ventricular stimulation pulse generator
56: Atrial sensing stage
58: Right ventricular sensing stage
60: Left ventricular sensing stage
66: Telemetry circuit
68: Activity sensor
62: Control unit
64: Memory circuit
70: Impedance determination unit
72: Constant current source
74: Voltage measuring unit
76: Impedance value determination unit
78: Evaluation unit
80: Nerve stimulation unit
82: Autonomic tone sensor
92: External programmer
90: Bedside Patient Messenger
100: Nerve stimulation cuff electrode
102: Nerve stimulation electrode lead
104: Nerve stimulation electrode pole

Claims

An implantable pulse generator system comprising
a nerve stimulation unit (80) for generation and delivery of vagal nerve stimulation pulses;
an activity sensor (68) for determining an exertion level of a user and generating a cardiovascular demand representing signal;
at least one autonomic tone sensor (82) for determining an autonomic status of the user and generating an autonomic status representing signal; and
a control unit (62) that is connected to the nerve stimulation unit, the activity sensor and the autonomic tone sensor and that is adapted to control the nerve stimulation unit depending on both, the cardiovascular demand representing signal and the autonomic status representing signal.
The implantable pulse generator system of claim 1, wherein the control unit (62) is adapted to control the nerve stimulation unit (80) to generate stimulation pulses having stimulation parameters that are configured to induce a vagus nerve stimulation (VNS) effect that is either an increase in vagal tone or an increase in sympathetic tone, depending on both the cardiovascular demand representing signal and the autonomic status representing signal.
The implantable pulse generator system of claim 2, wherein the control unit (62) and the nerve stimulation unit (80) are adapted to alter the effect of VNS by adjusting stimulation parameters including at least one of amplitude, pulse width, stimulation timing, and/or selection of stimulating electrodes.
The implantable pulse generator system of claim 2 or 3, wherein the control unit (62) is adapted to control the nerve stimulation unit (80) to generate stimulation pulses having stimulation parameters that are configured to induce an increase in vagal tone if the cardiovascular demand representing signal of the activity sensor (68) indicates a low demand and the autonomic status representing signal of the autonomic tone sensor (82) indicates an elevated sympathetic tone.
The implantable pulse generator system according to at least one of claims 2 to 4, wherein the control unit (62) is adapted to control the nerve stimulation unit (80) to generate stimulation pulses having stimulation parameters that are configured to induce a decrease in vagal tone and/or an increase in sympathetic tone, if the cardiovascular demand representing signal of the activity sensor (68) indicates an elevated cardiovascular demand and the autonomic status representing signal of the autonomic tone sensor (82) indicates a suppressed sympathetic tone.
The implantable pulse generator system according to at least one of claims 1 to 5, wherein the activity sensor (68) comprises an accelerometer.
The implantable pulse generator system according to at least one of claims 1 to 6, wherein the activity sensor (68) comprises a CLS sensor.
The implantable pulse generator system according to at least one of claims 1 to 7, wherein the activity sensor (68) comprises at least one of a minute ventilation sensor, a temperature sensor, a tissue oxygenation sensor, a sensor configured to process nerve signals that reflect the patient's intrinsic nerve activity, or a sensor configured to process signals that reflect the patient's state of blood pressure.
The implantable pulse generator system according to at least one of claims 1 to 8, wherein the autonomic tone sensor (82) is configured to process IEGM signals.
The implantable pulse generator system according to at least one of claims 1 to 9, further comprising a nerve stimulation cuff electrode (100) having at least one nerve stimulation electrode pole (104).
The implantable pulse generator system of claim 10, wherein the cuff electrode has two, three or four nerve stimulation electrode poles (104).
The implantable pulse generator system of claim 10 or 11, wherein the control unit (62) and the nerve stimulation unit (80) are arranged in a generator housing (42) of an implantable pulse generator (10), said implantable pulse generator (10) being connected to the cuff electrode (100) via a nerve stimulation electrode lead (102) comprising at least one electric conductor that electrically connects the nerve stimulation unit with the nerve stimulation electrode pole.
A method for vagal nerve stimulation, the method comprising:
determining an exertion level;

determining an autonomic status level;

delivering nerve stimulation pulses depending on both, the determined exertion level and the autonomic status level.
The method of claim 13, wherein nerve stimulation pulses having stimulation parameters that are configured to induce an increase in vagal tone are delivered if the cardiovascular demand representing signal of the activity sensor indicates a low demand and the autonomic status representing signal of the autonomic tone sensor indicates an elevated sympathetic tone.
The method of claim 13 or 14, wherein nerve stimulation pulses having stimulation parameters that are configured to induce a decrease in vagal tone and/or an increase in sympathetic tone are delivered, if the cardiovascular demand representing signal of the activity sensor indicates an elevated cardiovascular demand and the autonomic status representing signal of the autonomic tone sensor indicates a suppressed sympathetic tone.